1-substituted-4-[3-(9-xanthylidene)-propyl] piperazines and 1-substituted-4-[3-(10-thiaxanthylidene) propyl]-piperazines



United States Patent 1 SUBSTITUTED 4 [3 (9 XANTHYLIDENE) PROPYL'JPIPERAZINES AND 1 SUBSTITUTED 4 [3 (10 TI-IIAXANTHYLIDENE)PROPYL]- PIPERAZINES Guido E. Bonvicino, Pearl River, N.Y., and Robert A. Hardy, Jr., Ridgewood, NJ., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed July 18, 1957, Ser. No. 672,578

5 Claims. (Cl. 260-240) This invention relates to new organic compounds and more particularly is concerned with novel l-substituted-4 l3-(9-xanthylidene)propyl]piperazines and l-substituted- 4-[3-(10-thiaxanthylidene)propyll piperazines which may be represented by the following general formula:

CHr-N H N-R wherein X represents an oxygen or sulfur atom; R represents a hydrogen atom, a halogen atom such as chlorine and bromine, a lower alkoxy radical such as methoxy, ethoxy, etc.; and R represents a lower alkyl radical such as methyl, ethyl, propyl and butyl. The compounds of this invention are valuable tranquilizing agents and consequently are useful in the chemotherapy of diseases of the psyche. The compounds, in addition, are useful as analgesics.

The compounds of this invention are made by dehydration of tertiary alcohols of the structure:

wherein X, R and R have the meaning hereinbefore defined.

The ease of dehydration varies widely. With some of the novel compounds aqueous mineral acids such as hydrochloric acid, sulfuric acid, etc., at room temperature, effect the dehydration. Other members of this series, particularly the thiaxanthylidene compounds, are more re sistant to dehydration. In such case, more vigorous dehydrating agents such as thionyl chloride, phosphorus oxychloride and the like may be used.

The intermediate tertiary alcohols are conveniently prepared by a Grignard reaction using a l-substituted-4- (3-halopropyl)piperazine, magnesium and a substituted xanthone or thiaxanthone. The conditions for this reaction are not critical. A variety of solvents, commonly employed for Grignard reactions, such as ether, benzene, toluene, and xylene can be used. The useful temperature range varies widely. For convenience, the refluxing temperature of the solvent is generally used to insure completion of the reaction in a reasonable time. After the reaction is substantially complete, which usually requires from about 7 to 30 hours, the Grignard complex is decomposed. If desired, the l-substituted -4-[3-(9-hydroxy- 9-xanthyl)propyl]piperazine intermediates can be isolated from the organic phase by decomposition of the Grignard complex with neutral or alkaline reagents. In general, the l-substituted-4-[3-(9-hydroxy 9 xanthyl)- propyllpiperazines must be isolated as the free .bases because of their facile dehydration in the presence of mineral acids under mild conditions. The l-substituted-4- [3- (lO-hydroxy-IO-thiaxanthyDpropyl]piperazines, however, are relatively more resistant to dehydration and are frequently isolated as their mineral acid salts. The intermediate tertiary alcohol may be reacted -in situ with dehydrating agents as described above. The resulting 1 substituted 4 [3 (9 xanthylidene)propyl]piperazines and l substituted 4 [3 (10 thiaxanthylidene) propyllpiperazines are ordinarily isolated as the dihydrochloride salts in crystalline form. However, they may be purified further by recrystallization from various organic solvents such as the lower aliphatic alcohols.

Other therapeutically useful acid addition salts such as the sulfate or acetate may be similarly made with other acids as, for example, sulfuric acid, acetic acid, etc.

Suitable .1 substituted 4 (3 halopropyl)piperazines which may be used in forming the novel compounds here.- in are l-methyl-4-(3-chloropropyl)piperazine, .1-ethyl-4- (3-chloropropyl)piperazine and the like.

Among the suitable xanthones and thiaxanthones which may be used in'reaction with the piperazines referred to above to produce the novel compounds of this invention, there may be mentioned xanthone, 2-methoxyxanthone, 2-chloroxanthone, 4-bromoxanthone, Z-ethoxyxanthou, Z-thiaxanthone, Z-chlorothiaxanthone, 2-methoxythiaxanthone, and 2-bromothiaxanthone.

The process by which the novel compounds may be prepared is illustrated schematically below, wherein in the reaction scheme, X, R and R have the meaning hereinbefore given.

- Ether or dehydrating agent The invention will be described in greater detail in conjunction with the following specific examples.

' milliliters" of ether over a period of ten minutes. Only a amount of magnesium dissolves. l The. reaction flask is then warmed for afew'minutes and 'treated'with a'suspension of 7.84 grams of xan tho ne in 100milliliters of anhydrousbenzeneand 40 milliliters ofether; The reaction mixture is then refluxedwith constant stirring for twentyhours,' coole'd and decomposed with 100 ml. of 'cold 10% aqueous' ammonium chloride. The ether- EXAMPLE 4 p I -methyl-4- [3 -(2-methoxy-J O-Ihiaxanthylidene) propyl lpiperazine dihydrochloride 1 methyl 4 [3 (2methoxy-10-thiaxanthylidene)- propyllpiperazine dihydrochloride is prepared by reacting 2.4 grams of magnesium, 17.7 grams of l-methylA-(B- chloropropyl)piperazine and ,12.1 grams of -2-methoxythiaxanthone by the Grignard reaction as described in Example '1. The product obtained 'is 1-methyl-4-[3-(2- chloro IO-hydroxy thiaxanthyl)propyllpiperazine;

it melts 'at 112-115 C. Dehydration is accomplished as follows: 'four and one halfgrams of this product, are disbenzene layer-is-lsepai'atedgand the aqueous layer 'exa tractediwith ether. The ether washes are combined with theoriginal ether-benzeneilayer and washed with water. The organic layer is extracted with l *N'aqueous hydrochloric acid. The aqueous extract is washed withether hydrous hydrogen chloride; gas,;then evaporated to dryi and then'm'ade alkaline with potassium'carbonate, while ness. The residue is recrystallized fromlabsolute ethanol,

yielding product which decomposes at 243C. 'After auotherrecrystallization from absoluteethanol the product decomposes at 252 C. 1;

r EXAMPLE-2 1 V by the Grignard reaction as-described in Example 1.

The dihydrochloride salt is'prepared by treating an. alcoholic solution of the crude base with two molar. equivalents of alcoholic hydrogen chloride; e.g., 1.7 grams of L i I 1 the crude base is dissolved in 10 milliliters o f absolute ethanol and treated with 3.85 milliliters. of 2.6l.N alcoholic hydrogen chloride. The crystalline saltwhich separates is recrystallized from 15 milliliters 'of absolute ethanol, yielding a. product which softens at 209 and decomposes at 211213'C.

' EXAMPLE-3;" :1

1 methyl-4-[3 2.- 1;1om 1O thiaxanthylidene)- propyl]piperazine dihydrochloride is prepared by reacting 2.4 grams of magnesium, 17.7 grams of 1-methyl-4-(3- chloropropyl)piperazine and 12.3 grams of Z-chlorothiaxanthone by the Grignard reaction previously de- 7 scribed in Example 1." 'The dihydrochloride salt isisolated as described in Example 2; e.g., 3 grams of the crude base in 20 milliliters of absolute ethanol is treated with 6.2 milliliters of 2.61 N alcoholic hydrogen chloride.

The'dihydrochloride salt is isolated and recrystallized' twice from absolute ethanol. This product softens at 7 220 and decomposes at 247-249 C.

solvedin 15 milliliters of concentrated hydrochloricacid and 45 milliliters of glacial acetic acid. The solution is heated under reflux for three hours; The solution is cooled and dilutedwith millilitersof water and made strongly alkaline with 3--N sodium hydroxide (pH 11). The dehydrated base is extracted several times with ether. The ether extracts are combined and washed with water and dried over anhydrous potassium carbonate. The dried extract'is eva'poratedjto dr ynessfleaving3 .7 grams of residue. product is dissolved in 20 milliliters of absolute ethanol.v and treated with" 7.7- milliliters of 2.61 N alcoholic hydrogenchloride. "The solution is'cooled in an ice bath and upon standing for a few hours, a crystalline product separates. After two recrystallizations from absolute ethanol the 1-methyl-4-[3-(2-methoxy-10- thiaxanthylidene)propyl]piperazine dihydrochloride decomposes at 225-226 C.

' We claim:

l. A compound selected from the group consisting of 1-substituted 4 [3-(9-xanthylidene)propyllpiperazines and l-substituted 4 [3-(10 thiaxanthylidene)propyllpiperazines, corresponding to the' formula: a

HPN', .H NT-R and acid addition salts thereof wherein X represents a member of the group consisting of oxygen and sulfur atoms, R represents a member of the-group consisting of hydrogen, halogen, and lower alkoxy radicals, and R represents a lower alkyl radical.

2. 1-methyl-4-[3 (9 xanthylidene)propyllpiperazine. 3. l-methyl 4 [3-(2 -'methoxy 9 xanthylidene)- 2,861,987 1 Martin etaLllv j Noe-25,1 58 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-SUBSTITUTED - 4 - (3-(9-XANTHYLIDENE)PROPYL)PIPERAZINES AND 1-SUBSTITUTED - 4 - (3-(10-THIAXANTHYLIDENE)PROPYL)PIPERAZINES, CORRESPONDING TO THE FORMULA: 